For one condition, the drugs came before the disorder

Amanda LaFleur, 37, of Denver, pictured with her son, Mathieu, suffered severe premenstrual symptoms since she was 14. Drugs did not provide relief so she elected to have her ovaries removed two years ago, which eliminated her symptoms.(Photo: Family photo)

Story Highlights

For many years, psychiatrists debated whether premenstrual dysphoric disorder, a severe form of PMS, should be recognized as a mental disorder.

Long before it was recognized as such in 2013, the FDA approved four drugs – including three antidepressants – to treat it.

A Milwaukee Journal Sentinel/MedPage Today investigation into the emergence of PMDD found evidence of drug company influence — and money — at virtually every step along the way.

Beginning in 2000, the FDA approved four drugs to treat premenstrual dysphoric disorder, a form of PMS said to be so severe that it qualifies as a psychiatric condition.

The hitch: It wasn't even recognized as a mental disorder until 13 years after first drug treatments were on market.

The drug approvals started less than two years after an unusual private meeting involving six officials from the U.S. Food and Drug Administration and four executives from Eli Lilly. The drug company’s lucrative patent on the antidepressant Prozac was about to expire and the executives had a new market in mind.

The 1998 meeting in Washington, D.C., was funded by Lilly and included 16 researchers exploring the condition, called PMDD.

There was strong disagreement over the condition, which the American Psychiatric Association had determined needed more study before it could be included in its manual defining mental disorders and symptoms.

That didn’t stop the meeting participants.

On their own, they determined PMDD was a distinct clinical disorder and declared that a class of antidepressant drugs known as selective serotonin reuptake inhibitors — a group including Prozac — were effective at treating it.

Lilly rebranded Prozac, changing the pill’s colors from green and yellow to pink and purple, and giving it a more feminine-sounding name — Sarafem.

Sarafem won FDA approval. So did three drugs from other companies: the antidepressants Zoloft (2002) and Paxil (2003), and the birth control pill Yaz (2006).

It wouldn't be until 2013 that the American Psychiatric Association formally recognized PMDD as a distinct psychiatric condition — a determination that was based on the recommendation of a panel on which nearly 70% of the members had drug company ties.

By then, drug companies had created a major new market. For instance, annual sales of Yaz peaked at $782 million in 2009, until dropping off after reports linked drugs in its class to dangerous blood clots.

The new market was built on a disputed condition, inflated estimates of how many women had it and drugs that carry severe risks and side effects, such as suicidal thinking.

Conclusions from that 1998 meeting were presented as a consensus. But one participant whose name appears on the paper said she never agreed that PMDD was a mental condition or that antidepressants should be used to treat it.

To this day, Sally Severino, an emeritus professor of psychiatry at the University of New Mexico, said she holds an opposite view. There never has been convincing evidence to prove either contention, she said in an interview.

She also offered her explanation for why the 1998 meeting was called.

“We were on the road to making this a mood disorder,” she said. “I think the pharmaceuticals had a lot of influence.”

Drugs first, disorder second

A Milwaukee Journal Sentinel/MedPage Today investigation into the emergence of PMDD found evidence of drug company influence — and money — at virtually every step along the way. It is one of a series of new disorders promoted by drug companies and treated with expensive, often dangerous, drugs.

What stands out about PMDD is that so much of the effort to promote the condition began long before it was recognized as a psychiatric disorder.

On its face, the meeting — which over the years has received scant public attention — was unusual.

“For the FDA to participate in this behind closed doors is very troubling,” said Michael Carome, director of the health research arm of Public Citizen, a watchdog organization. “It had a direct outcome on their (Lilly’s) financial bottom line.”

Lilly spokesman J. Scott MacGregor said a check of company records showed the meeting was called after Lilly met with FDA officials “who suggested it would be useful” to convene experts to determine if PMDD was a distinct disorder.

In an email, FDA spokeswoman Lauren Shaham defended the agency’s participation in the meeting and noted that a public discussion of the condition was held about a year later at the official FDA meeting on whether to approve Sarafem.

“FDA staff often participate in various external meetings with the drug development, physician, academic, and patient communities in many disease areas,” she said.

Critics say it is unusual for a small group of doctors to independently determine what is or is not a medical or psychiatric condition. That typically falls to medical societies or associations, though earlier Journal Sentinel/MedPage Today investigations found those groups frequently accept money from pharmaceutical companies.

A leader of the 1998 meeting, and the lead author of the subsequent paper, was Jean Endicott, a psychologist at Columbia University. Endicott, who is not a medical doctor, has had longstanding financial ties to companies that manufacture drugs for PMDD, including Eli Lilly, GlaxoSmithKline and Pfizer.

In the paper, published in the Journal of Women’s Health, the researchers said they looked at evidence such as published studies and listened to presentations from experts. They also considered “perceptions” about the condition.

When the FDA advisory committee meeting was held five months later, the results of the paper were not presented by any authors of the paper. Instead, the meeting's findings were handled by a doctor from the Society of Women’s Health Research — the group that convened the meeting after getting money from Lilly to pay for it.

Endicott also spoke, a transcript of the meeting shows, this time on behalf of Lilly.

One of the panel members asked: Why wasn't PMDD recognized by the psychiatric community?

“There were other issues going on, and this is always a committee kind of decision in a general setting in which political issues do get considered,” Endicott said.

After unanimous support from the panel, the FDA approved the drug.

Allen Frances, chairman of the American Psychiatric Association panel that in 1994 had decided not to elevate PMDD to an official condition, said he was “puzzled” at the time about the FDA approval of the drug. The condition, he said, “wasn’t ready for prime time.”

In an interview, he said it was “absolutely absurd for the FDA, in secret meetings with drug companies, to make a decision that would be contrary” to what the psychiatric community had decided about PMDD.

"That's not the way regulators are supposed to work,” he said. “It's the fox guarding the hen house."

Similarly, guidelines to help doctors decide how to treat PMDD were issued before the condition was even recognized as a psychiatric disorder.

Typically such guidelines are issued by medical societies or other groups. In this case, the 2006 guidelines were issued by a small group of researchers and paid for by GlaxoSmithKline — the maker of Paxil.

The guidelines proclaimed antidepressants, such as Paxil, were “the treatment of choice” for PMDD.

The guidelines were published in the Journal of Women’s Health, the same journal that published the findings from the 1998 meeting.

While the guidelines did not disclose financial conflicts of the eight authors, at least six are known to have worked for companies that make drugs used to treat PMDD, according to a Journal Sentinel/MedPage Today analysis of other published work by the authors.

One was Endicott, the Columbia University psychologist who led the 1998 meeting. She has worked as a consultant and speaker to drug companies going back more than a decade. In an interview, she said that has not biased her work.

“I’ve never felt dependent on them or that I had to please them,” she said.

A dubious number

At the time the FDA was considering Sarafem for approval, estimates claimed as many as 8% of premenopausal American women had PMDD, a figure that would represent about 6 million women.

But independent researchers say those calculations are flawed.

Even before it was formally recognized, the criteria for PMDD said a woman must have at least five of 11 symptoms, such as feeling angry, irritable, depressed or anxious, and having mood swings.

Sarah Gehlert, of the Institute of Public Health at Washington University in St. Louis, said she was suspicious that the various estimates were not following the definition.

“If it existed, we wanted it to be recognized,” she said. “On the other hand, we didn’t want to glorify something that didn’t exist.”

In 2009, Gehlert’s team studied 1,247 women from rural and urban communities in Illinois and Missouri and followed them through two menstrual cycles to determine if they met the criteria.

The finding: Only 1.3% of premenopausal women may have PMDD in any given year.

That means just under 1 million women in the United States, not 6 million.

“We did become convinced that some women had PMDD,” Gehlert said, “but we could also see that it had the potential to harm women if it became a quick-and-dirty diagnosis.”

While the FDA approved Sarafem for the not-yet-existent diagnosis of PMDD in 2000, European regulators were more cautious.

In withholding approval, the European Medicines Agency cited concerns that women with less severe symptoms might be wrongly diagnosed and treated with a potent antidepressant with potentially dangerous side effects. The drug has never been approved for such a condition in the European market.

“The pharma industry went out trying to promote the condition so that more women self-presented with this disorder, and consequently, put pressure on doctors to prescribe medications for them,” said Saddichha Sahoo, a psychiatrist at Ipswich Hospital in Brisbane, Australia, who wrote a 2010 paper about disease mongering in psychiatry, which included PMDD.

Early television ads for Sarafem showed a woman angrily trying to claim a shopping cart at the grocery store. The ad described symptoms of premenstrual syndrome and urged women to “Think again: it could be PMDD.”

A period of uncertainty

In the years leading up to the approval of Sarafem, there was strong disagreement among mental health experts, ranging from those who wanted it removed from the diagnostic manual altogether to those who argued for moving it into the main section as an official mood disorder.

In the late 1990s, Eli Lilly brought Nada Stotland, a prominent psychiatrist and women’s health expert, to its headquarters in Indianapolis. Stotland strongly opposed FDA approval of Sarafem as well as the idea of establishing PMDD as a mental disorder.

Stotland said she felt the company was hoping it could get her to change her mind.

She recalled company officials argued that getting the drug approved could help destigmatize the disorder. But, in an interview, Stotland said she wasn’t buying it — then or now.

She said she feared that making the condition a mental disorder would lead to women with problems such as stress or depression getting lumped into a diagnosis of PMDD.

What’s more, since Prozac was merely repackaged and renamed as a treatment for PMDD, she felt it would make it easier for family practice doctors and gynecologists to prescribe it without doing the kind of psychological assessment that was needed to rule out other mental problems.

Another concern was that having it in the diagnostic manual could help mask what otherwise might be a woman’s justified reaction to abuse and mistreatment.

Stotland, who served as president of the American Psychiatric Association from 2008 to 2009, said she fought its inclusion in the manual throughout her career.

“I gave up, essentially," Stotland said, once the condition was approved in the 2013 edition.

A spokeswoman for the psychiatric association said the decision to include PMDD in its most recent edition of the manual went through several layers of review. She noted committee members were not allowed to have received more than $10,000 in payments from drug companies in the previous year.

Kimberly Yonkers, a professor of psychiatry at Yale School of Medicine and a member of the broader task force that oversaw the change, said members “were aware of prior controversies” about PMDD but “relied on scientific findings as guiding principles.”

Drugs carry risks

All antidepressants used to treat PMDD — Sarafem, Zoloft and Paxil — carry the FDA’s most stringent black box warning for increased risk of suicidal thinking.

The drugs also carry a substantially increased risk of causing lack of energy, sleepiness and decreased libido.

While studies funded by drug companies showed antidepressants worked in about 60% of women with PMDD, one clinical trial found basic calcium supplements were effective in 55% of women with premenstrual symptoms.

No rigorous studies have been done that show the long-term effectiveness of the antidepressants.

In practice, the effectiveness seems to wear off after about six months, according to Amanda LaFleur, executive director of the National Association for Premenstrual Dysphoric Disorder.

Meanwhile, she said, for many women the only other approved drug, Yaz, only makes symptoms worse.

In two clinical trials sponsored by its maker, Yaz reduced PMDD symptoms, but not much more than a placebo.

Women who took Yaz showed a 37.5-point improvement on a symptom scale that had a maximum of 126 points, but those who received a placebo had a 30-point improvement.

The drug’s effectiveness beyond three menstrual cycles was not tested.

LaFleur said she started her association in 2013 to help women sift through all of their options.

For her part, she suffered from severe premenstrual symptoms since the age of 14, but found the drugs to be ineffective. Two years ago, at age 35, she took a more extreme route — removal of her ovaries.

“Now, I have no symptoms whatsoever,” she said.

Treating PMDD with birth control pills that include the drug drospirenone, such as Yaz, is especially concerning because there are pills that pose less risk, said Diana Zuckerman, president of of the National Center for Health Research, a nonprofit think tank that analyzes health research.

“Safer drugs are available to effectively treat PMDD,” she said. “How bad is your PMDD that you are willing to put your life at risk?”

John Fauber is a reporter for the Milwaukee Journal Sentinel. Kristina Fiore and Matthew Wynn are reporters for MedPage Today.

This story was reported as a joint project of the Journal Sentinel and MedPage Today, which provides a clinical perspective for physicians on breaking medical news at medpagetoday.com.

Read the investigation

To read past stories in the Illness Inflation investigation, and to explore an interactive database of other everyday conditions that have become medical issues, go to jsonline.com/illnessinflation.